A Combined Treatment with Tacrolimus (FK506) and Recombinant Tissue Plasminogen Activator for Thrombotic Focal Cerebral Ischemia in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window

The authors evaluated the therapeutic efficacy of tacrolimus (FK506), administered alone or in combination with recombinant tissue plasminogen activator (t-PA), on brain infarction following thrombotic middle cerebral artery (MCA) occlusion. Thrombotic occlusion of the MCA was induced by a photochemical reaction between rose bengal and green light in Sprague-Dawley rats, and the volume of ischemic brain damage was determined 24 hours later. Intravenous administration of tacrolimus or t-PA dose-dependently reduced the volume of ischemic brain infarction, whether administered immediately or 1 hour after MCA occlusion. When tacrolimus or t-PA was administered 2 hours after MCA occlusion, each drug showed a tendency to reduce ischemic brain damage. However, combined treatment with both drugs resulted in a significant reduction in ischemic brain damage. On administration 3 hours after MCA occlusion, tacrolimus alone showed no effect, and t-PA tended to worsen ischemic brain damage. However, the combined treatment with both drugs not only ameliorated the worsening trend seen with t-PA alone, but also tended to reduce ischemic brain damage. In conclusion, tacrolimus, used in combination with t-PA, augmented therapeutic efficacy on brain damage associated with focal ischemia and extended the therapeutic time window compared to single-drug treatments.

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A Combined Treatment With Tacrolimus (FK506) and Recombinant Tissue Plasminogen Activator for Thrombotic Focal Cerebral Ischemia in Rats: Increased Neuroprotective Efficacy and Extended Therapeutic Time Window

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200210000-00008 ◽

2002 ◽

pp. 1205-1211 ◽

Cited By ~ 19

Author(s):

Masashi Maeda ◽

Yasuhisa Furuichi ◽

Noriko Ueyama ◽

Akira Moriguchi ◽

Natsuki Satoh ◽

...

Keyword(s):

Cerebral Ischemia ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Time Window ◽

Focal Cerebral Ischemia ◽

Combined Treatment ◽

Recombinant Tissue Plasminogen Activator ◽

Tissue Plasminogen ◽

Neuroprotective Efficacy ◽

Therapeutic Time Window

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Wide therapeutic time window for Rho-kinase inhibition therapy in ischemic brain damage in a rat cerebral thrombosis model

Brain Research ◽

10.1016/j.brainres.2007.11.050 ◽

2008 ◽

Vol 1193 ◽

pp. 102-108 ◽

Cited By ~ 43

Author(s):

Shin-ichi Satoh ◽

Yoshinori Toshima ◽

Asako Hitomi ◽

Ichiro Ikegaki ◽

Minoru Seto ◽

...

Keyword(s):

Brain Damage ◽

Time Window ◽

Rho Kinase ◽

Cerebral Thrombosis ◽

Ischemic Brain Damage ◽

Kinase Inhibition ◽

Ischemic Brain ◽

Thrombosis Model ◽

Therapeutic Time Window

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Co-administration of liposomal fasudil and tissue plasminogen activator ameliorated ischemic brain damage in occlusion model rats prepared by photochemically induced thrombosis

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.11.107 ◽

2018 ◽

Vol 495 (1) ◽

pp. 873-877 ◽

Cited By ~ 9

Author(s):

Tatsuya Fukuta ◽

Yosuke Yanagida ◽

Tomohiro Asai ◽

Naoto Oku

Keyword(s):

Plasminogen Activator ◽

Brain Damage ◽

Tissue Plasminogen Activator ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Occlusion Model ◽

Tissue Plasminogen

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Effect of Combined Treatment With Curcumin and Candesartan on Ischemic Brain Damage in Mice

Journal of Stroke and Cerebrovascular Diseases ◽

10.1016/j.jstrokecerebrovasdis.2010.03.008 ◽

2011 ◽

Vol 20 (6) ◽

pp. 541-548 ◽

Cited By ~ 12

Author(s):

Azza S. Awad

Keyword(s):

Brain Damage ◽

Combined Treatment ◽

Ischemic Brain Damage ◽

Ischemic Brain

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Genetic Deletion of mGlu3 Metabotropic Glutamate Receptors Amplifies Ischemic Brain Damage and Associated Neuroinflammation in Mice

Frontiers in Neurology ◽

10.3389/fneur.2021.668877 ◽

2021 ◽

Vol 12 ◽

Author(s):

Federica Mastroiacovo ◽

Manuela Zinni ◽

Giada Mascio ◽

Valeria Bruno ◽

Giuseppe Battaglia ◽

...

Keyword(s):

Brain Damage ◽

Metabotropic Glutamate Receptors ◽

Wild Type ◽

Ischemic Brain Damage ◽

Α Subunit ◽

Ischemic Brain ◽

Infarct Region ◽

Metabotropic Glutamate ◽

Mca Occlusion ◽

Genetic Deletion

Backgroud: Type-3 metabotropic glutamate (mGlu3) receptors are found in both neurons and glial cells and regulate synaptic transmission, astrocyte function, and microglial reactivity. Here we show that the genetic deletion of mGlu3 receptors amplifies ischemic brain damage and associated neuroinflammation in adult mice. An increased infarct size was observed in mGlu3−/− mice of both CD1 and C57Black strains 24 h following a permanent occlusion of the middle cerebral artery (MCA) as compared to their respective wild-type (mGlu3+/+ mice) counterparts. Increases in the expression of selected pro-inflammatory genes including those encoding interleukin-1β, type-2 cycloxygenase, tumor necrosis factor-α, CD86, and interleukin-6 were more prominent in the peri-infarct region of mGlu3−/− mice. In contrast, the expression of two genes associated with the anti-inflammatory phenotype of microglia (those encoding the mannose-1-phosphate receptor and the α-subunit of interleukin-4 receptor) and the gene encoding the neuroprotective factor, glial cell line-derived neurotrophic factor, was enhanced in the peri-infarct region of wild-type mice, but not mGlu3−/− mice, following MCA occlusion. In C57Black mice, the genetic deletion of mGlu3 receptors worsened the defect in the paw placement test as assessed in the contralateral forepaw at short times (4 h) following MCA occlusion. These findings suggest that mGlu3 receptors are protective against ischemic brain damage and support the way to the use of selective mGlu3 receptor agonists or positive allosteric modulators in experimental animal models of ischemic stroke.

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